The JNK-dependent CaMK pathway restrains the reversion of committed cells during osteoclast differentiation.

Osteoclastogenesis involves the commitment of macrophage-lineage precursors to tartrate-resistant acid phosphatase-positive (TRAP+) mononuclear pre-osteoclasts (pOCs) and subsequent fusion of pOCs to form multinuclear mature osteoclasts. Despite many studies on osteoclast differentiation, little is known about the signaling mechanisms that specifically mediate the osteoclastic commitment. In this study, we found that inhibition of JNK at the pOC stage provoked reversion of TRAP(+) cells to TRAP(-) cells. The conversion to TRAP(-) cells occurred with concomitant return to the state with higher expression of macrophage antigens, and greater activity of phagocytosis and dendritic-differentiation potential. JNK inhibition at the pOC stage reduced NFATc1 and CaMK levels, and addition of active NFATc1 partially rescued the effect of JNK inhibition. In addition, the level of NFATc1 was decreased by knockdown of CaMK by RNAi and by catalytic inhibition of CaMK, which both caused the reversion of pOCs to macrophages. These data suggest that JNK activity is specifically required for maintaining the committed status during osteoclastogenesis and that the CaMK-NFATc1 pathway is the key element in that specific role of JNK.